Fusion between the viral and target cell membranes is an obligatory step for the infectivity of all enveloped viruses, and blocking this process is a clinically validated therapeutic strategy. Viral fusion is driven by specialized proteins which, although specific to each virus, act through a common mechanism, the formation of a complex between two heptad repeat (“HR”) regions. The HR regions are initially separated in an intermediate termed “prehairpin”, which bridges the viral and cell membranes, and then fold onto each other to form a 6-helical bundle (“6HB”), driving the two membranes to fuse. HR-derived peptides can inhibit viral infectivity by binding to the prehairpin intermediate and preventing its transition to the 6HB. The antiviral activity of HR-derived peptides differs considerably among enveloped viruses. For weak inhibitors, potency can be increased by peptide engineering strategies, but sequence-specific optimization is time-consuming. It has been possible to increase potency without changing the native sequence, by the attachment of a cholesterol group to the HR peptide (“cholesterol-tagging”) and by combining cholesterol-tagging with dimerization of the HR-derived sequence.
Many fusion inhibitors of enveloped viruses have been reported to date. To exemplify the process of such development, the generation and testing of inhibitors of the Measles virus (“MV”) is reported. MV is one of the most infectious microorganisms known, and continues to cause extensive morbidity and mortality worldwide. Despite the availability of a vaccine and the measles initiative launched by WHO, UNICEF, and their partners to increase vaccine coverage, MV has not been eradicated and caused 140,000 deaths globally as recently as 2010 (Simons et al., “Assessment of the 2010 Global Measles Mortality Reduction Goal: Results from a Model of Surveillance Data,” Lancet 379:2173-8 (2012)), making it one of the major causes of mortality among vaccine-preventable diseases. Measles cases in North America have increased in recent years, with hundreds of confirmed cases in 2011; European eradication of MV is also far behind the expected deadlines, and numerous outbreaks have occurred during the last few years (Moss et al., “Measles,” Lancet 379:153-64 (2012) and De Serres et al., “The Largest Measles Epidemic in North America in a Decade—Quebec, Canada, 2011: Contribution of Susceptibility, Serendipity and Super-Spreading Events on Elimination,” J. Infect. Dis. 2012)). Therefore, although vaccination is essential for the control of measles, it alone may not be sufficient (Moss et al., “Measles,” Lancet 379:153-64 (2012) and Plemper et al., “Measles Control—Can Measles Virus Inhibitors Make a Difference?” Curr. Opin. Invest. Drugs 10:811-20 (2009)) and should be complemented by the use of antiviral therapy to restrict virus dissemination (Plemper et al., “Measles Control—Can Measles Virus Inhibitors Make a Difference?” Curr. Opin. Invest. Drugs 10:811-20 (2009)).
Complications of MV infection occur in up to 40% of cases, and those involving the Central Nervous System (“CNS”) are rare but serious. Primary measles encephalitis occurs in 1-3 of 1000 infected patients, with recovery of infectious virus from the cerebrospinal fluid or brain (Hosoya, “Measles Encephalitis: Direct Viral Invasion or Autoimmune-Mediated Inflammation?” Internal Med. 45:841-2 (2006) and Buchanan et al., “Measles Virus and Associated Central Nervous System Sequelae,” Seminars Ped. Neurol. 19:107-14 (2012)). Another CNS complication, acute postinfectious encephalomyelitis, also occurs during or shortly after acute measles but seems to be associated with an autoimmune etiology, and virus is not isolated. Subacute sclerosing panencephalitis (“SSPE”) occurs in 4-11 of 100,000 cases of acute measles, causing progressive dementia, seizures, and ataxia (Allen et al., “The Significance of Measles Virus Antigen and Genome Distribution in the CNS in SSPE for Mechanisms of Viral Spread and Demyelination,” J. Neuropathol. Exper. Neurol. 55:471-80 (1996)). Another form of progressive MV-induced CNS disease, known as measles inclusion body encephalitis (“MIBE”), occurs in immunosuppressed patients 1 to 6 months following measles infection, and is characterized by seizures, motor and sensory deficits, and lethargy, with either an acute or a subacute fatal course. Nonrestricted virus replication, due to an absent or decreased immune response, results in cytolytic viral replication in the brain tissue (Buchanan et al., “Measles Virus and Associated Central Nervous System Sequelae,” Seminars Ped. Neurol. 19:107-14 (2012); Urbanska et al., “Spread of Measles Virus Through Axonal Pathways into Limbic Structures in the Brain of TAP1−/− Mice,” J. Med. Virol. 52:362-9 (1997); and Norrby et al., “Measles Virus in the Brain,” Brain Res. Bulletin 44:213-20 (1997)).
There are no specific therapies for these complications of CNS infection, often with lethal outcomes (Makhortova et al., “Neurokinin-1 Enables Measles Virus Trans-Synaptic Spread in Neurons,” Virology 362:235-44 (2007); O'Donnell et al., “Blue Moon Neurovirology: The Merits of Studying Rare CNS Diseases of Viral Origin,” J. Neuroimmune Pharmacol. 2010; Young et al., “Making it to the Synapse: Measles Virus Spread in and Among Neurons,” Curr. Top Microbiol. Immunol. 330:3-30 (2009); and Reuter et al., “Measles Virus Infection of the CNS: Human Disease, Animal Models, and Approaches to Therapy,” Med. Microbiol. Immunol. 2010)). Although treatment of SSPE has been attempted with a broad spectrum of anti-viral drugs, including ribavirin, interferons, and isoprinosin, complete remission has not been achieved (Moss et al., “Measles,” Lancet 379:153-64 (2012); Plemper et al., “Measles Control—Can Measles Virus Inhibitors Make a Difference?” Curr. Opin. Invest. Drugs 10:811-20 (2009); Lin et al., “Prolonged Persistence of Measles Virus RNA is Characteristic of Primary Infection Dynamics,” Proc. Nat. Acad. Sci. U.S.A. 109:14989-94 (2012); and Griffin et al., “Measles Virus, Immune Control, and Persistence,” FEMS Microbiol. Rev. 36:649-62 (2012)). Therefore, in addition to vaccination, establishment of effective prophylactic therapies for MV CNS infection is important.
The present invention is directed to overcoming these and other deficiencies in the art.